Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1104115 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28789261_1.fastq.gz | Fastqsanger.gz | |||
| SRR28789261_2.fastq.gz | Fastqsanger.gz | |||
| SRR28789262_1.fastq.gz | Fastqsanger.gz | |||
| SRR28789262_2.fastq.gz | Fastqsanger.gz | |||
| SRR28789263_1.fastq.gz | Fastqsanger.gz |
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Project description:Inhibition of adipocyte triglyceride lipase (ATGL/PNPLA2) activity in insulin resistance and non-alcoholic fatty liver disease is an attractive therapeutic target. This study evaluated the impact of Atglistatin-mediated ATGL inhibition on non-alcoholic steatohepatitis (NASH) development in diabetic and hyperlipidaemic mice. Streptozotocin-injected male mice were fed an HFD to induce NASH. We analysed liver histology, hepatic lipid content, immunohistochemistry, RNA sequencing, and serum biochemistry. Mechanistically, we treated Caco2 cells, human primary ileum-derived organoids, and HepG2 ATGL KD cells with the novel human ATGL inhibitor NG-497 and WY14643. Atglistatin reduced body and liver weights, total liver lipid content, and improved blood sugar levels consistent with improved liver enzymes, histological liver injury, and NAFLD activity scores. Mechanistically, Atglistatin reduced Cpt1a and Abca1, suggesting impaired Ppara signalling that favours hydrophilic bile acids (BA) synthesis since Cyp7a1, Cyp27a1, and Cyp2c70 were increased while Cyp8b1 was reduced. Accordingly, Intestinal lipid transporters, Abca1 and Cd36, were reduced, consistent with the reduction of liver TAG species, mostly linoleic acids. We used human-specific ATGL inhibitor NG-497 to validate the mouse findings. The NG-497-treated human primary ileum organoids and Caco2 cells showed reduced ATGL, ABCA1, FATP5, CD36, and MTTP. PPARa signalling was impaired in the ileum organoids and HepG2 treated with NG-497 and in HepG2 ATGL KD since PPARa, CPT1a, AOX, ABCA1, and CYP8B1 were reduced, and CYP7A1 increased. Inhibition of ATGL activity reduces the availability of ligands for Ppara activation leading to impaired Ppara signalling, which translate into hydrophilic BA that interferes with dietary lipid absorption, improving metabolic disturbances. The validation with the NG-497 should open a new clinical avenue for NAFLD clinical trial and treatment.
2024-11-01 | GSE236832 | GEO
Project description:Inhibition of adipose triglyceride lipase alleviates non-alcoholic steatohepatitis in diabetic mice via impaired PPARa signalling favouring hydrophilic bile acid composition
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Project description:The role and molecular mechanisms of intermittent fasting (IF) in non-alcoholic steatohepatitis (NASH) and its transition to hepatocellular carcinoma (HCC) are unknown. Here, we identified that an IF 5:2 regimen (two non-consecutive days of food deprivation per week), initiated in the active phase of mice, prevents NASH development as well as ameliorates established NASH and fibrosis without affecting total calorie intake. Furthermore, the IF 5:2 regimen also blunted NASH-HCC transition when applied therapeutically in two independent models of diet-induced NASH and NASH-HCC. The timing (7pm-7pm > 7am-7am), length (24h > 12h) and number (5:2 > 6:1) of fasting cycles as well as the type (WD / CDHFD) of NASH diet were all critical parameters determining the effectiveness of the fasting benefits. Combined proteome, transcriptome and metabolome analyses identified that PPARα and glucocorticoid signalling-induced phosphoenolpyruvate carboxykinase 1 (PCK1) act co-operatively as hepatic executors of the fasting response by promoting fatty acid catabolism and gluconeogenesis while suppressing anabolic lipogenesis. In line, PPARα targets and PCK1 were reduced in human NASH. Notably, only fasting during the active phase (7pm-7pm) of mice robustly induced glucocorticoid signalling in hepatocytes including PCK1 expression; while both active and inactive phase (7am-7am) fasting induced free fatty acid-induced PPARα signalling, highlighting the increased efficacy of fasting during the active phase. However, hepatocyte-specific glucocorticoid receptor (GR) deletion only partially abrogated the hepatic fasting response, illustrating the need for both glucocorticoid-induced PCK1 expression and free fatty acid-induced PPARα activation for mediating the benefits of fasting. In support, the combined knockdown of Ppara and Pck1 in vivo abolished the beneficial outcomes of fasting against inflammation and fibrosis, confirming their causal relationship in integrating systemic signalling in hepatocytes. Moreover, overexpression of Pck1 alone or together with Ppara in vivo lowered hepatic triglycerides and steatosis upon Western-diet feeding. Altogether, our data support that the IF 5:2 regimen could be a promising and viable intervention against NASH and subsequent liver cancer.
2024-05-29 | GSE255356 | GEO
Project description:Background & Aims: Somatic and germline CIDEB mutations are associated with protection from chronic liver diseases. The mechanistic basis and whether CIDEB suppression would be an effective therapy against fatty liver disease remain unclear. Methods: 21 CIDEB somatic mutations were introduced into cells to assess functionality. In vivo screening was used to trace Cideb mutant clones in mice fed normal chow, western (WD), and choline-deficient, L-amino acid-defined, high-fat (CDA-HFD) diets. Constitutive and conditional Cideb knockout mice were generated to study Cideb in liver disease. Isotope tracing was used to evaluate fatty acid oxidation and de novo lipogenesis. Transcriptomics, lipidomics, and metabolic analyses were utilized to explore molecular mechanisms. Double knockout models (Cideb/Atgl and Cideb/Ppara) tested mechanisms underlying Cideb loss. Results: Most CIDEB mutations showed that they impair function, and lineage-tracing showed that loss-of-function clones were positively selected with some, but not all fatty liver inducing diets. Cideb KO mice were protected from WD, CDA-HFD, and alcohol diets, but had the greatest impact on CDA-HFD induced liver disease. Hepatocyte-specific Cideb deletion could ameliorate disease after MASLD establishment, modeling the impact of therapeutic siRNAs. Cideb loss protected livers via increased β-oxidation, specifically through ATGL and PPARa activation. Conclusions: Cideb deletion is more protective in some types of fatty liver disease. β-oxidation is an important component of the Cideb protective mechanism. CIDEB inhibition represents a promising approach, and somatic mutations in CIDEB might predict the patient populations that might benefit the most.
2025-08-06 | GSE294945 | GEO
Project description:Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic diseases globally and nonalcoholic steatohepatitis is its progressive stage with limited therapeutic options. Here a role for intestinal peroxisome proliferator-activated receptor α (PPARα)-fatty acid binding protein 1 (FABP1) in obesity-associated metabolic syndrome, fatty liver and nonalcoholic steatohepatitis via modulating dietary fat absorption was uncovered. Intestinal PPARα is highly activated accompanied by marked upregulation of FABP1 by high-fat diet (HFD) in mice and obese humans. Intestine-specific PPARα or FABP1 disruption in mice decreases HFD-induced obesity, fatty liver and nonalcoholic steatohepatitis and intestinal PPARα disruption fails to further decrease obesity and NASH. Chemical PPARα antagonism improves metabolic disorders depending on the presence of intestinal PPARα or FABP1. Translationally, GW6471 decreases human PPARα-driven intestinal fatty acid uptake and therapeutically improves obesity in PPARA-humanized, but not Ppara-null, mice. These results suggest that intestinal PPARα-FABP1 axis could be a therapeutic target for NASH.
2022-09-01 | GSE190140 | GEO
Project description:Optimal treatment for nonalcoholic steatohepatitis (NASH) has not yet been established, particularly for individuals without diabetes. We examined the effects of metformin, commonly used to treat patients with type 2 diabetes, on liver pathology in a non-diabetic NASH mouse model. Eight-week-old C57BL/6 mice were fed a methionine- and choline-deficient (MCD) + high fat (HF) diet with or without 0.1% metformin for 8 weeks.
2012-02-21 | E-GEOD-35961 | biostudies-arrayexpress
Project description:Gene expression profiling in 6 tissues (white adipose tissue (WAT), brown adipose tissue (BAT), cardiac muscle (CM), liver (LIV), kidney (KID), skeletal muscle (SM)) from ATGL(-/-) mice versus wildtype (ATGL+/+) mice.
2008-02-03 | E-MARS-8 | biostudies-arrayexpress
Project description:Nonalcoholic steatohepatitis (NASH) is epidemiologically associated with obesity and diabetes and can lead to liver cirrhosis and hepatocellular carcinoma if left untreated. The intricate signaling pathways that orchestrate hepatocyte energy metabolism and cellular stress, intrahepatic cell crosstalk, as well as interplay between peripheral tissues remain elusive and are crucial for the development of anti-NASH therapies. Herein, we reveal E3 ligase FBXW7 as a key factor regulating hepatic catabolism, stress responses, systemic energy homeostasis, and NASH pathogenesis, with attenuated FBXW7 expression as a feature of advanced NASH. Multiomics analysis and pharmacological intervention showed that loss of FBXW7 function in hepatocytes disrupts a metabolic transcriptional axis conjointly controlled by the nutrient-sensing nuclear receptors ERRa and PPARa, resulting in suppression of fatty acid oxidation, elevated ER stress, apoptosis, immune infiltration, fibrogenesis, and ultimately NASH progression. These results provide the foundation for developing alternative strategies co-targeting ERRa and PPARa for the treatment of NASH.
2023-08-18 | GSE205845 | GEO
Project description:Obesity-associated lipid overload triggers non-alcoholic fatty liver diseases (NAFLD), which in part may be driven by alterations of regulatory transcription networks and hepatocyte-selective epigenomes. Here we demonstrate that G protein pathway suppressor 2 (GPS2), a subunit of the nuclear receptor corepressor (NCOR)/ histone deacetylase 3 (HDAC3) complex, is a central component of such networks and accelerates the progression of non-alcoholic steatohepatitis (NASH). In hepatocyte-specific Gps2 knockout mice, loss of GPS2 alleviated the development of diet-induced steatosis and fibrosis and caused activation of lipid catabolic genes. By determining differential cistromes, epigenomes and transcriptomes in wild-type, single and double knockout mice, we identified the lipid-sensing nuclear receptor PPARa as a direct target of GPS2. We also provide evidence that in hepatocytes, unlike in macrophages, GPS2 acts in concert with the NCOR subunit of the corepressor complex. By analyzing the liver transcriptomes of human patients, we found that GPS2 expression positively correlated with the expression of NASH/fibrosis signature genes. Collectively, our data suggest that the GPS2-PPARa partnership in hepatocytes may influence the development of NASH/fibrosis in mice and in humans.
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Project description:We demonstrated that ACBP/DBI inhibition impaired hepatocarcinogenesis in NASH/MASH-driven HCC models. To further investigate its potential mechanisms at transcriptional level in NASH/MASH-driven HCC models, we performed Bulk RNA-seq analyses with liver tissues from the following three models, namely, (i) WD/CCl4 with tamoxifen inducible ACBP/DBI knout mice (Dbi-/- mice, Dbi+/+ mice as control) for in total 27 weeks; (ii) WD/CCl4 with KLH/KLH-ACBP immunized mice for in total 34 weeks; and (iii) HFD/DEN with KLH/KLH-ACBP immunized miceI for a total of 36 weeks.
2025-04-18 | GSE255799 | GEO